A neuroendocrine feedback loop in C. elegans males integrates food detection and biological sex to modulate chemoreceptor expression and behavioral flexibility

Dynamic integration of internal and external cues is essential for flexible, adaptive animal behavior. In , biological sex and feeding state regulate expression of the food-associated chemoreceptor , contributing to plasticity in food detection and the decision between feeding and exploration. In adult hermaphrodites, expression is high; in well-fed adult males, expression is low, promoting exploratory mate-searching behavior. Food-deprivation transiently activates male expression, heightening food sensitivity and reducing food-leaving. Here, we identify a neuroendocrine feedback loop that sex-specifically regulates in response to food deprivation. In well-fed males, insulin-like (IIS) and TGFβ signaling repress expression. Upon food deprivation, is directly activated by DAF-16/FoxO, the canonical IIS effector. The TGFβ ligand DAF-7 acts upstream of IIS, and, likely because of its sexually dimorphic expression in the nervous system, links feeding to only in males. Surprisingly, these responses to food deprivation are not triggered by internal metabolic cues, but rather by the loss of sensory signals from food. In the presence of inedible food, males become metabolically starved but express levels of and comparable to those of well-fed males. Further, exposing food-deprived males to inedible food is sufficient to restore low expression. Food signals are detected by a small number of sensory neurons whose activity non-autonomously regulates expression, IIS, and . Thus, adult males employ a neuroendocrine feedback loop that integrates food detection and genetic sex to dynamically modulate chemoreceptor expression and sensory behavior.